RESUMO
Previously, it had been reported that 6-(phosphonodifluoromethyl)-2-naphthoic acid binds to the protein-tyrosine phosphatase PTP1B with its 2-carboxyl group interacting only indirectly through a bridging water molecule. Reported herein is a family of new analogues that utilize acylsulfonamido functionality both to mimic this water of hydration and to provide an additional new site for elaboration not found in the parent carboxyl-containing analogue. Target acylsulfonamides were prepared in two steps from commercially available primary sulfonamides, which were selected based on in silico screening for their potential ability to interact with one of three binding surfaces proximal to the PTP1B catalytic site. In general, modest potency enhancements were observed. Arylacylsulfonamides represent a structure-based extension of inhibitor design that may have broader utility in the development of PTP1B inhibitors.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/química , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Aminoácidos Acídicos/química , Animais , Sítios de Ligação , Simulação por Computador , Inibidores Enzimáticos/farmacologia , Enzimas/química , Humanos , Concentração Inibidora 50 , Mimetismo Molecular , Ligação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Relação Estrutura-Atividade , Sulfonamidas , Água/químicaRESUMO
Reported herein is the first enantioselective preparation of (2S,3R)-3-phenylpipecolic acid as a conformationally constrained phenylalanine analogue bearing N(alpha)-protection suitable for solid-phase peptide synthesis. Stereochemistries at both the 2- and 3-positions are derived inductively from a single chiral center provided by the commercially available Evans chiral auxiliary, (4S)-4-benzyl-1,3-oxazolidin-2-one. By constraining phi and chi(1) torsion angles, this novel amino acid analogue can serve as a useful tool for the induction of defined geometry in phenylalanine-containing peptides.
